1. Field of the Invention
This invention relates to intraoral medicament-releasing devices capable of slowly releasing an agent into the oral cavity, to a process of manufacturing such devices, and methods for the prevention and treatment of certain diseases including dental caries, incipient carious lesions and periodontal diseases. More particularly, the invention relates to a controlled rate-release device comprising an inner core containing a pharmaceutically acceptable agent and an outer layer of a saliva-insoluble, non-erodible rate-controlling membrane allowing water to enter into the inner core to dissolve the pharmaceutically acceptable agent which then diffuses through the rate-controlling membrane into the oral environment.
2. Reported Developments
Dental practitioners and their patients are aware of the importance of proper oral hygiene in maintaining healthy teeth and gums. Routine use of toothbrush, toothpaste, fluoride rinse and floss as well as periodic visits to the dentist to remove plaque and calculus from the root surfaces greatly contributes to such oral care maintenance. However, this routine must be kept diligently, and even then, it is only effective to a limited extent regarding certain oral conditions.
Dental caries and periodontal diseases are widespread chronic conditions. Caries is an infectious disease caused by bacteria. Bacteria metabolize fermentable carbohydrates to organic acids. The acids in close contact with the enamel cause enamel demineralization. Extensive demineralization leads to dental caries. Caries may be prevented by the frequent use of fluorides. Fluoride enhances enamel remineralization, increases tooth resistance to further acid attack, and arrest the progression of caries. Fluorides are employed in toothpastes, tablets, drops, mouth rinses and drinking water. Periodontal diseases are inflammatory conditions affecting the tooth supporting structures. Anaerobic bacteria proliferates in the gingival crevice, produce enzymes, toxins and noxious metabolites that accumulate in the gingival crevice. These bacterial by-products are irritating to the gingival tissue and initiate a localized inflammation. The inflamed tissues release enzymes that destroy the collagen supporting fibers and alveolar bone. If this process is left unchecked it will eventually lead to the exfoliation of tooth.
In addition to dental caries and periodontal diseases a certain segment of the population suffers from other ailments and conditions of the oral cavity.
Xerostomia, or dry mouth condition, is frequently caused by a dysfunction of the major salivary glands and is associated with a number of diseases. Xerostomia may also be caused by certain medication especially in the elderly. Radiation treatment of head and neck cancer may also result in xerostomia. Patients who undergo orthodontic treatment for various health and cosmetic reasons that require wearing of orthodontic devices experience white-spot enamel lesions around the orthodontic bands due to accumulation of plaque. Denture wearers experience irritation and painful lesions on the roof of the mouth as a result of which masticatory functions are impaired and the patients also develop digestive problems and nutritional deficiencies. Handicapped individuals are at a greater risk of developing rampant caries because of the physical limitations imposed by their handicaps and good oral hygiene.
Periodontal treatment utilizes mechanical debridement of tooth surfaces and root planning and scaling. Systemically administered antibiotics have also shown some promise as an antimicrobial measure.
These treatments, although effective against bacteria at the time of administration are not sufficiently long-lasting. Bacteria proliferates within hours in the oral cavity and condition leading to caries and periodontal disease reappear again. It is apparent that since these disorders are chronic, the duration of drug presence at the target site is critical in both prevention and therapy.
These conditions and ailments are treatable, since it has been shown that a low level of fluoride which constantly enriches the saliva has the potential to prevent the development of dental caries and associated conditions in the oral cavity. (See O. Fejerskov, A. Thylstrup and M. J. Larsen: Rational Use of Fluorides in Caries Prevention. A Concept Based on Possible Cariostatic Mechanisms. Acta Odontol Scand. 39(4): 241-249 (1981)). Accordingly, a fluoride-containing reservoir which can release fluoride at a constant rate to enrich the saliva with therapeutically effective levels of fluoride is required (See D. B. Mirth and W. H. Bowen. A Microbial Aspect of Dental Caries. Vol. 1 pp. 249-262, Information Retrieval Inc., Washington, D.C. (1976)).
It is also apparent that most of the currently marketed products to prevent rampant caries associated with xerostomia and other oral ailments are deficient for several reasons, such as lack of sustained-release fluoride, adequate patient compliance, unpleasant taste and cumbersomeness of application, lack of control of applied dosage and the potential toxic effect from the product being swallowed accidentally.
Although at present there are no commercially available products on the market based on long term sustained-release, controlled delivery principle, efforts are being made to provide such products as illustrated by the following references.
Slow-releasing devices to be attached to or placed around teeth or implanted into the gum are disclosed, for example, in U.S. Pat. Nos. 3,624,909; 3,688,406; 4,020,558; 4,175,326; 4,681,544, 4,685,883, 4,837,030 and 4,919,939. While these devices do deliver a medication into the oral cavity, they lack a controlled rate of delivery for extended time periods which is of utmost importance in the prevention and treatment of the heretofore mentioned diseases and conditions. For example, U.S. Pat. No. 4,837,030 discloses an orally administrable pharmaceutical composition comprising beads coated with an ultrathin layer of a polymer that erodes under gastric conditions. When suspended in water, more than 90% of the pharmaceutical agent is released from the composition between 20 to 90 minutes; U.S. Pat. No. 4,919,939 discloses a controlled release drug delivery system comprising a polymeric matrix which dissolves, releasing the drug contained therein within 10 to 18 hours, upon the action of the saliva.
Polymeric varnishes containing the antiseptic chlorhexidine or cetylpyridinium in ethylcellulose or polyurethane varnishes were found to be effective to prevent plaque formation. However, the antibacterial effects are short-term and the application of the varnishes has to be repeatedly performed by a dentist.
Hollow fibers and methacrylate slabs containing antibacterial agents, such as tetracycline, placed into periodontal pockets were also found effective. Lack of esthetics, pain and discomfort caused by such devices limit their use to only certain patients with extreme cases of periodontal disease.
A device for attachment to teeth and to deliver sodium fluoride or chlorhexidine at a controlled-rate was found effective in delivering the active substances at a constant linear rate. The device comprises a copolymer hydrogel of hydroxyethyl methacrylate and methyl methacrylate as the inner core which holds the active agents, while the outer layer, a copolymer of the same constituents at a different mole ratio controls the drug release rates. See D. B. Mirth et al, Development and In Vitro Evaluation of an Intra-Oral Controlled-Release Delivery System for Chlorhexidine, J. Dent. Res. August (1989); D. B. Mirth et al, Clinical Evaluation of an Intraoral Device for the Controlled Release of Fluoride, JADA, Vol. 105, November (1982).
While this system of delivery is excellent for fluoride and chlorhexidine, there is no process or method disclosed by which the device could be manufactured economically. Laboratory scale or hand-made small size devices of this type tend to be prohibitively expensive and unaffordable by that segment of the public which needs it the most. Also, there is no provision disclosed to tailor-make the device to deliver fluorides or chlorhexidine so that prophylactic or treatment requirements of patients could be satisfied allowing for different rates and duration of delivery. Furthermore, no process is taught by which uniform and predictable dosage could be assured.
Analogous to the controlled rate-release device for the prevention and treatment of dental diseases, the device of the present invention may be used for the prevention and treatment of other diseases which require slow and controlled rate-release of a pharmaceutically active agent. Such diseases include impotency, osteoporosis, tumors, drug abuse, yeast infection and the like. While slow release devices are well known and successfully utilized by the pharmaceutical industry in the form of topical dressings, such as wound and burn dressing, intra-oral devices proposed for long term delivery of drugs are few and provide insufficient duration of delivery at a constant rate. Typically, such devices, while capable of delivering medicaments, such as psychotropic agents, antispasmodics, anti-inflammatory agents, hormones, antibiotics and the like, deliver their active agents within ours or within a couple of days after their introduction into the oral cavity. An example of such devices is disclosed in U.S. Pat. No. 4,876,092.
The present invention solves these and other problems as will be discussed as the description of the invention proceeds.